TWI362391B - Process for the manufacture of fused piperazin-2-one derivatives - Google Patents

Description

1362391 IX. Description of the invention: [Technical field of invention] The present invention relates to a method for preparing a condensed six gas jet 2_ copper derivative of the general formula (1)

R4 wherein the definition of the group to V is as provided in the scope of the patent application and the specification, the invention is particularly directed to a process for preparing a 7,8-dihydro-kappa-6-indole derivative. [Prior Art] It is known from the prior art that acaridone is an anti-proliferative activity, a tongue. WO 03/020722 describes the use of dihydrobite-derivatives for the treatment of neoplastic diseases and methods for their preparation. The 7,8-dihydro-5hh6 derivative of formula (I) is an important intermediate product in the synthesis of these actives. Up to now, these derivatives have been produced by a method of reducing a nitro compound of the following formula (II), which results in a strong color mixture product, and thus requires laborious processing and purification. step. WO 96/36597 teaches the catalytic hydrogenation of a nitro compound using a noble metal catalyst by the addition of a ruthenium compound while revealing that the final product is a free amine & does not contain any internal amine. 105841.doc

(D 1362391 SUMMARY OF THE INVENTION, 8-Dihydrogen _ The object of the present invention is to provide an improved process for the preparation of a compound of the formula (1), in particular a 7 5H-bite-6-one derivative. The J 々 method on the compound of the formula (1) can solve the problems outlined in the text. ^ The invention thus relates to the preparation of the compound of the formula j

(I) where

The R R1 R3 representative is selected from the group consisting of gas, fluorine, bromine, methanesulfonyl, sulfonate, trifluoromethanesulfonyl, p-nonylbenzenesulfonyl, phenyl s(=o)- Representing nitrogen or a C1-C3 -alkyl group, representing hydrogen or a group selected from the group consisting of an optionally substituted CrCu-alkyl group, a c2 Ci2.alkenyl group, a C2_C!2-alkynyl group, and a CVCi4.aryl group, Or a C3-C12-cyclolyl' C3-C12-cycloalkenyl group, a C7-C12-polycycloalkyl group, a C7-C12-polycyclic group 'Cs-, which is optionally substituted and/or bridged. a group consisting of a c12-spirocycloalkyl group and a saturated and unsaturated C3-C12-heterocyclic palladium group having from 1 to 2 heteroatoms, 105841.doc 1362391 R4, R5 may be the same or different The group ' represents hydrogen or optionally substituted ^-匕-alkyl, or R4 and R5 together represent an alkyl bridge of 2 to 5 members which may contain 1 to 2 heteroatoms, or R4 and R3 Or R5 and R3 together represent a saturated and unsaturated C3_C4_alkyl bridge, which optionally contains 1 heteroatom, and Αι and 八2 may be the same or different groups, representing _ch= or -N=, Preferably, -N=, wherein compound R2 of formula II

(Π) where r1-r5 and Αι '八2 have the stated definition and R represents Ci-c4-yard, a) hydrogen hydrogenation in the presence of a hydrogenation catalyst, and b) addition of steel 'iron or vanadium Compounds in which steps a) and b) can occur simultaneously or sequentially. In a preferred method, the hydrogenation of the compound of formula II is carried out directly in the presence of a hydrogenation catalyst and copper iron or a starvation compound to form a compound of formula I.

10584i.doc 1362391 In a preferred method, the first product of the formula is first obtained after the first hydrogenation step a), which can be isolated as appropriate.

(in) subsequently further reduced in the presence of a hydrogenation catalyst and a copper, iron or vanadium compound to form a compound of formula I R Η

The method of group consisting of turn, Ji and Lei Shi is also preferred. Platinum is especially good. The platinum may be used in the form of a metal or an oxide state (e.g., platinum oxide) on a support such as activated carbon, cerium oxide, aluminum oxide, calcium carbonate, or similar, barium sulfate, titanium oxide, oxidation. Lock, iron oxide lead oxide, sulfuric acid wrong 4 barium carbonate, and depending on the situation, additional sulfur sulfur ^ boat. Preferred carrier materials activate carbon, dioxin or oxidation. Preferred copper compounds are those in which the steel is in an oxidized state or a ruthenium, for example; a copper compound such as CuCb CuCl2, CuBr, cuB〇, cun

The preferred iron compound of CuS04 is 105841.doc 1362391. In which iron is oxidized or HI, such as iron halides, such as FeCl2, FeCl3, FeB〇, FeBr3, FeF2 or other iron compounds such as FeS〇4 , Fep〇4 or Fe(aCaC)2. Preferred vanadium compounds are compounds in which vanadium is in the oxidized state of ruthenium, π, π, IV or V, such as inorganic or organic compounds or complexes, such as v203 'v2o5 'v2〇4 'Na4V〇4, NaV〇3 , NH4V〇3, v〇ci2, v〇Cl3, V〇S〇4, VCl2, vci3, bis(1_phenyl_13 butyl sulphuric acid vinegar) _ 酸 ΙΙΙ (ΙΙΙ) [ν (·) 3] or ethoxylated vinegar vinegar oxidation (IV) [vo (acae) 2]. Ethyl acetoacetate (IV) [VO (acac) 2] is particularly preferred. The copper 'iron or IM conjugate can be used as it is at the beginning of the hydrogenation reaction' or after the intermediate of the formula (III) is formed. A method in which the amount of the hydrogenation catalyst added is between 0.1 and 10% by weight based on the compound of the formula (II) used is also suitable. same. A suitable method is one in which the amount of the copper, iron or cerium compound is between 〇1 and 1% by weight based on the compound of the formula (II) used. Preferably, the method further comprises the step wherein the reaction is carried out in a solvent selected from the group consisting of amphoteric aprotic solvents (e.g., dimethylamine, dimethylacetamide, hydrazine, methylpyrrolidone). , dimethyl sulfoxide or cyclobutyl hydrazine alcohol (eg methanol, ethanol hydrazine 1-propanol, 2 · propanol, butane and pentane various isomeric alcohols); ether (eg diethyl ether 'methyl third Butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran 'dioxane or dimethoxyethane (for example, 2-ethyl acetate or 2-butyl acetate); ketone (such as acetone) , acetophenone: methyl isobutyl ketone); carboxylic acid (such as acetic acid); non-polar solvent (such as toluene, xylene, cyclohexane or methylcyclohexane), and acetonitrile, two 105841.doc .1362391 a group consisting of methyl chloride and water. A mixture of solvents can be used. The preferred method also includes a reaction temperature between 〇.〇 and 150 ° C, particularly preferably between 20 ° C and 10 0 °. Between C. The preferred method also includes a pressure of 1 bar to 1 bar of hydrogen therein. The invention further relates to a compound of formula (III)

R2 OH

Wherein R1 to R5 have the definitions described. Preferred compounds of formula (III) are those in which, and are the same and represent • N = 0. These reactions are carried out in a conventional manner, for example, by precipitation and crystallization by extraction purification steps.

The compounds according to the invention may be in the form of individual optical isomers, mixtures of individual mirror isomers, non-mirror isomers or racemates, tautomeric forms and free bases or acids. Corresponding acid addition salts (such as, for example, an acid containing hydrogen dentate plus 譬 譬 # 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯 氯The form of liquefied monoacetic acid or methanesulfonic acid) exists. Part of the group) has examples of yards containing 1 to 1-4 carbon atoms (including those of other groups of 12 carbon atoms (preferably 1 to 6 carbon atoms, 105841.doc 1362391) Branched and unbranched alkyl groups are, for example, methyl, ethyl, propyl, butyl 'pentyl, hexyl'heptyl'octyl, decyl, decyl and decyl. Unless otherwise There are statements 'otherwise the above-mentioned names propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl and dodecyl are all possible isomeric forms. For example, propyl includes two The isomeric group is n-propyl and isopropyl, and the butyl includes n-butyl, iso-butyl, t-butyl and t-butyl groups, and the pentyl group includes isopentyl, neopentyl and the like.

Among the above alkyl groups, one or more hydrogen atoms may be optionally substituted by other groups. For example, these alkyl groups can be substituted by fluorine. All of the ruthenium atoms of the alkyl group may also be replaced by all.

Examples of alkyl bridges are branched and unbranched alkyl groups containing from 2 to 5 carbon atoms, such as ethyl, propyl, and exopropyl propyl-n-butyl, unless otherwise stated. A bridging group of 'iso-butyl' dibutyl and tert-butyl groups. Particularly preferred are the bridging groups of ethyl, #propyl and butyl. In the above alkyl bridging group, 'unless c atoms may be optionally substituted by - or more than one hetero atom selected from oxygen, nitrogen or sulfur. Examples of alkenyl groups (including those which are part of other groups) have 2 12 carbon atoms (preferably 2·6 carbon atoms, preferably 2 to 3 carbon atoms) branched and unbranched County, premise that it has at least one double bond ^ shown below: B County, (four) base, Τ 基, 戊 ^ ^ unless otherwise stated 'other than the above named acryl, butyl, etc. Includes all possible isomeric forms. For example, 'butyryl group includes 1. butylon, 2_. alkenyl, 3-butenyl, i•methyl is still rare, soil 1 fluorenyl-2-propenyl, T storm-1-propenyl, 2-methyl Department, 咕, A storm propylene and ^ ethyl-1-vinyl. 105841.doc 8 •12- . . . to observe the above alkenyl orders, unless otherwise stated, one or more hydrogenogens may be replaced by other groups as appropriate. For example, all of the hydrogen atoms of these alkenyl groups which may be substituted by a tooth atom may also be substituted. Examples of alkynyl groups (including those which are part of other groups) have branched and unbranched alkynyl groups containing from 2 to 12 carbon atoms, provided that they have at least one reference group such as an ethynyl group, Propynyl, butynyl, pentynylhexynyl and the like are preferably ethynyl or propynyl.

Among the above alkynyl groups, unless otherwise stated, one or more hydrogen atoms may be substituted by the group to which they are derived. For example, these alkynyl groups can be gas replacers. All hydrogen atoms of the alkynyl group may also be substituted.

The aryl group represents an aromatic ring system containing from 6 to 14 carbon atoms, preferably 6 or 1 carbon atoms, preferably a phenyl group, which may, for example, have one or more of the following, unless otherwise stated. Substituents: 〇H, n〇2, cn, 〇Me, _〇CHF2 '-OCf3, dentate (preferably or gas), c"Ci〇·alkyl (preferably CrC5·alkyl, especially Is ^-(:3-alkyl, especially methyl or soil) 〇Ci C3-morphyl (car jia is _〇_methyl or _〇_ethyl), _c〇〇h ' -C00- Ci-C4-alkyl (preferably _c〇〇methyl or c〇〇_ethyl)-CONH2. Examples of cycloalkyl groups are cycloalkyl groups containing 3 to 12 carbon atoms, such as cyclopropyl, cyclobutane Or a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group, preferably a cyclopropyl group, a cyclopentyl group or a cyclohexyl group, and each of the above cycloalkyl groups may optionally have one or more substituents. , for example: n〇2 , CN, OMe ' , -0 (^3 or dentate (preferably fluorine or chlorine), Ci_ c 〇-alkyl (preferably aCl_C5_alkyl, especially Ci_C3_ Alkyl, especially preferably 105841.doc • 13- 8 1362391 methyl or ethyl) ,-0-CrC3-alkyl (preferably -〇-methyl or 〇ethyl), -COOH, -C00-CVC4-alkyl (preferably -C00.methyl or -coo-ethyl) Or -conh2. A preferred substituent of the cycloalkyl group is 〇, 〇H, methyl or F. Examples of cycloalkenyl groups are cycloalkenyl groups having 3 to 12 carbon atoms which have at least one double bond, for example a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group or a cycloheptenyl group, preferably a cyclopropenyl group, a cyclopentenyl group or a cyclohexenyl group, and each of the above-mentioned base groups may be optionally used. With _ or more than one substituent. = ◦ represents an example of an oxo-heterocyclic group bonded by a double bond, unless stated in the definition, from 3 to 12 members (preferably 5 6- or 7) a saturated or unsaturated heterocyclic ring which may contain a hetero atom of gas, oxygen or sulfur, such as a tetranitrogen domain, a tetrazole, a γ·丁内 Sa α辰南γ·, a second Oxolane, tetrahydrobine, dioxane, dihydro far thiophene, sulfur, disulfide, 峨 琳 琳, pyrrolidine "Bizolin'..., Lin " rice squirt, four Hey, six hydrogen (four) ten wells, (four) " than the brown, six hydrogen wells, three, , four calls, hualin, thio dailin, diazepam (diaZePam), ten wells, tetrahydrogen well base 'different' sitting and, than bite, preferably yin, 吼 blowing β ^ 'Which Pyridine, hexahydropyridine or hexahydropyridinium, and the heterocyclic ring may optionally have, for example, a c Γ q column such as I 丨-C4.alkyl, preferably a methyl, ethyl or propyl substituent. An example of a hospital base is a double-, triple-, tetra- or pentacyclic ring-burning group as the case may be substituted, such as ping, 2?, ligating ''octane' 2,2,1-heptane or adamantane . An example of a polycyclic ring is a bridge-dependent and/or substituted 8-membered double-, 105841.doc if a substrate, preferably a double or a tricyclic, if its # contains at least one In the case of a double bond, for example, the ice sheet is thin. The f example of the spiro group is a spiro c5.c12-alkyl group which is optionally substituted. ** represents a, gas, bromine or moth, preferably I, chlorine or desert, especially preferably gas 0. The substituent R may be selected from the group consisting of gas, fluorine, sulphur, sulphur, and sulphur. The group of the group consisting of a sulphur group and a sulphur group is preferably gas. The substituent R may represent hydrogen or a Ci_C3 alkyl group, preferably a gas. The substituent R3 may represent hydrogen, or a group selected from the group consisting of Ci_Ci2_alkyl, C2_Ci2. alkenyl, C2_Cl2-alkynyl, and C6-Cl4.aryl optionally substituted, preferably phenyl, Or a C3_Ci2 cycloalkyl group (preferably cyclopentyl) which is optionally substituted and/or bridged, CVCt cycloalkenyl, c7_Ci2•polycycloalkyl, C7_ ciz-polycycloalkenyl, Cs-C a group of a group consisting of a spirocycloalkyl group and a saturated and unsaturated c3_Ci2_heterocycloalkyl group (which contains 1 to 2 hetero atoms). The substituents R4, R5 may be the same or different groups and may represent hydrogen, or optionally substituted Ci-C6-alkyl, or R4 and R5 together represent 2 to 2 heteroatoms. The 5_ member's base bridge, or R4 and R3 or R5 and R3 together represent a saturated and unsaturated C3_C4_alkyl bridge' which may optionally contain 1 heteroatom β VIII! And 八2 may be the same or different groups, representative, preferably -Ν=. 105841.doc 1362391

R6 may represent a C^-C4.alkyl group, preferably a methyl group or an ethyl group. The compound of the formula (III) can be produced according to a method known in the literature, for example, a synthesis method similar to that described in WO 03/020722. The compound of the formula (I) can be specifically obtained by the following synthesis examples. Bright. However, these examples are merely examples for explaining the flow of the present invention, and the scope of the present invention is not limited to the contents of the examples. Flow chart 1

Synthesis of (7R)-2-chloro-8-cyclopentyl_7-ethyl-5-carbyl-7,8-dihydro-5Η-嗓 bit-6-嗣 105841.doc 16. 8 1362391

30 g (84-2 mmol) of 1 was dissolved in 3 liters of tetrahydrofuran and 3 g of Pt/C (5%) was added. The gasification reaction mixture was starved for 5 hours under hydrogen pressure of 4 bar. The catalyst was transferred out and washed with about 30 ml of four gas. Decompression • Concentrate the filtrate by evaporation. 25.6 g of product 2 were obtained as a yellow solid. ^-NMR (400 MHZ) (DMSOd6): δ 11.〇5 (bs 1H); y.85 (s 1H); 4.47-4.45 (dd 1H); 4.16-4.08 (t lH); 1.95-1.67 (m Synthesis method of 10H); 0.80-0.73 (t 3H) (7R)-2 - gas-8·cyclodecyl-7-ethyl-7,8-di-argon- 5H-嗓

3 5.22 g (17.6 mmol) of 2 was dissolved in 55 ml of tetrahydrofuran. Add 520 mg of Pt-C (5%) and 250 mg of acetal pyruvate to oxidize vanadium (IV). The reaction mixture was argonized under hydrogen pressure at 20 ° C and 4 bar for six hours. The catalyst was filtered off and washed with about 15 ml of tetrahydrofuran. The filtrate was concentrated under reduced pressure in the form of evaporated 105841.doc -17-8 1362391. 5.0 g of product 3 was obtained as a yellow powder. H-NMR (400 MHz) (DMS 〇d6): δ 11.82 (bs 1H); 7.57 (s 1H); 4.24-4,21 (dd 1H); 4.17-4.08 (m ih); 1.97-1.48 (ml〇 H); 0.80-0.77 (t 3H). Synthesis of (7R)-2- gas-8-cyclopentyl-7-ethyl-7,8-dihydro-5U-indole-6-one 70 grams of pt/C (5%) was added to 700 Glucose (1·96 mol) was dissolved in 7 ml of tetrahydrofuran. The reaction mixture was hydrogenated under a hydrogen pressure of 35 ° C and 4 bar for 2.5 hours until the hydrogen uptake was stopped. The autoclave was opened and 35 g of vanadyl pyruvate oxide vanadium (IV) was added. The mixture was at 3 5 . Hydrogenation was carried out for 2.5 hours under hydrogen pressure at 4 bar. Filter and wash the residue with tetrahydrofuran. The mash is concentrated by evaporation under reduced pressure. The residue was dissolved in 2.7 5 liters of acetone and the residue was precipitated by adding an equal amount of demineralized water. The resulting solid was sucked and washed with a mixture of propylene/water (1:1) and then washed with a third butyl decyl ether. After drying, 551 mg of the product (7R)-2- gas-8-cyclopentyl-7-hexyl-7,8-dihydro-5H-indole-6-one was obtained in a 30 g method (84 m). 1 of Mohr) was dissolved in 300 ml of tetrahydrofuran. Add 3 grams of Pt/C (5%) and 1.5 grams of ruthenium ruthenium acetate (iv). The reaction mixture was hydrogenated at 5 ° C and 4 bar under hydrogen pressure for 24 hours until the reaction was complete. The solution was filtered, and the residue was washed with tetrahydrofuran, and the mixture was concentrated and evaporated. The residue was dissolved in 11 8 mL of propylidene and the residue was precipitated by adding an equivalent amount of demineralized water. The resulting solid was taken up as a suction and washed with a mixture of acetone/water (1:1) and then washed with hexanes. After drying, 18 grams of product 3 were obtained. Synthesis of (7R)-2- gas-7- 6-yl-8-isopropyl-7,8-dihydro-5H-bite-6·_ 105841.doc 1S 8 1362391

10 g (316 mmol) of 4 was dissolved in 800 ml of tetrahydrofuran and 200 ml of isopropanol. 10 g of Pt/C (5 ° / 〇) and 5 g of acetamidopropionate vanadium (IV) oxide were added. The reaction mixture was hydrogenated at 35 ° C and 4 bar under hydrogen pressure for 24 hours until the reaction was completed. The solution was filtered and the filtrate was allowed to completely evaporate until crystallization began to form. 150 ml of isopropanol was added and the suspension was heated to 70-80 ° C until completely dissolved. After the addition of 6 liters of demineralized water, the product began to crystallize. Filter by suction and wash with demineralized water. 68 g of product 5 were obtained after drying. 'H-NMR (400 MHz) (DMSOd6): δ l〇.8l (bs 1H); 7.56 (s 1H); 4.37-4.24 (m 2H); 1.89-1.65 (m 2H); 1.34-1.31 (m

6H); 0.80-0.73 (t 3H) 10584 丨.doc 19-

Claims (1)

Application for Patent Collection _ W Japanese Repair (More) Original Patent Application No. 094142312 Eastern Text Cai 4^·] Scope Replacement (1〇〇 Preparation of Generalization | Material ^_Method, _ Announcement (I) wherein R represents a group selected from the group consisting of gas, fluorine, bromine, decanesulfonyl, ethanesulfonyl, difluoromethanesulfonyl, p-toluenesulfonyl, Cl^spo)- and phenyl S ( =〇)-Composed group, R2 represents hydrogen or ^-匕-alkyl, R represents hydrogen or is selected from Ci_Ci2_alkyl which is optionally substituted, C2_Cu-thinyl 'C2_Cl2_alkynyl and C6_Cm_aryl a group consisting of a group selected from the group consisting of optionally substituted and/or bridged c3_c12-cycloalkyl, c3_C12-cycloalkenyl 'c7-c12-polycycloalkyl, c7_Cl2_polycycloalkenyl, a group of Cs-C^-spiroline groups and a group of saturated and unsaturated c3_c12_heterocyclic alkyl groups (which contain 1 to 2 heteroatoms), R4, R5 may be the same or different groups, Represents hydrogen or optionally substituted q-cv alkyl, or R and R5 together represent a 2 to 5 membered alkyl bridge which may contain 1 to 2 heteroatoms, or R4 and R3 or R5 and R3 - a C3_C4_alkyl 105841-1000928.doc 1362391 bridge representing saturated and unsaturated, which may optionally contain 1 heteroatom, And VIII and VIII may be the same or different groups, representing _ch= or -N=, which is characterized by a compound of formula II R2 Wherein r to r5 'VIII! and 八2 have the definition as claimed and R6 represents CVCV alkyl, a) hydrogenation using hydrogen in the presence of a hydrogenation catalyst, and b) addition of a compound of copper, iron or vanadium, Where steps a) and b) can occur simultaneously or sequentially. The method of claim 1 is characterized in that a compound of copper is added in step b). The method of claim 1 is characterized in that the compound 0 of iron is added in step b). The method of claim 1, characterized in that a sharp compound is added in step b). 5. The method of any one of clauses 1 to 4, wherein the steps a) and b) are continued. 6_, as in the case of claim 5, which is characterized by the first step a), first obtaining the intermediate product of 105841-1000928.doc 1362391, which can be isolated as appropriate. And a compound of the formula I is obtained after the subsequent step b). The method of any one of claims 1 to 4 is characterized in that the steps of illusion and 匕 are performed simultaneously. 8. The method of any one of claims 1 to 4, characterized in that the hydrogenation is selected from the group consisting of ruthenium, rhodium, iridium, platinum, palladium and nickel. 9. The method according to any one of claims 1 to 4, characterized in that the hydrogenation catalyst is added in an amount of between 〇丨 and 1 〇 weight 〇 / based on the compound of the formula (II) used. The method of any one of items 1 to 4, characterized in that the amount of copper, iron or a compound added is between 〇〇1 and 1 (% by weight) based on the compound used (<()). The reaction is such that the solvent is selected from the group consisting of amphoteric acid, a non-polar solvent, characterized in that the reaction temperature is 11, and the aprotic solvent is a mixture of a solvent or a solvent of any one of the methods of claim 4 to 4, A group consisting of an alcohol, an ether, an ester, and a mixture of methylene chloride and water. The method of any one of claims 1 to 4 is between 〇C and 15〇. 〇. It is characterized by a hydrogen pressure of 13. The method of claim 10, wherein the method of the method of any one of the methods of the invention is in the form of a method of preparing a compound of the formula I, and a method of preparing a compound of the formula I. HIN NIR o, -r4r (1) wherein R1 to R5, VIII and A2 have the definitions as defined in claim 1, characterized in that the compound of the formula III is hydrogenated using hydrogen in the presence of a hydrogenation catalyst and a copper, iron or vanadium compound. reaction (III) wherein R1 to R5 and A! > A2 have the definitions as set forth in claim 1. 10584M000928.doc 4-